Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity.
Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity.
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特发性肺纤维化和COVID-19严重程度之间的共同遗传病因。
DOI：
10.1016/j.ebiom.2021.103277
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发表时间：
2021-03
期刊：
影响因子：
11.1
通讯作者：
Feenstra B
中科院分区：
文献类型：
--
作者：
Fadista J;Kraven LM;Karjalainen J;Andrews SJ;Geller F;COVID-19 Host Genetics Initiative;Baillie JK;Wain LV;Jenkins RG;Feenstra B
特发性肺纤维化（IPF）是一种复杂的肺部疾病，以进行性肺瘢痕形成为特征。重度COVID-19与严重肺炎相关，并与IPF有许多共同的主要风险因素。本研究旨在确定IPF与重度COVID-19之间的遗传相关性，并评估IPF遗传风险增加对COVID-19严重程度的潜在因果作用。采用连锁不平衡（LD）评分回归估计IPF与COVID-19严重程度之间的遗传相关性。我们对IPF与COVID-19的因果关系进行了孟德尔随机化（MR）研究。在先前的全基因组关联研究（GWAS）中，与IPF易感性相关的遗传变异（P<5 × 10−8）被用作工具变量（IV）。这些IV对COVID-19严重程度的影响估计值来自COVID-19宿主遗传学倡议的GWAS荟萃分析（4，336例病例和623，902例对照）。我们检测到IPF与COVID-19严重程度的正遗传相关性（rg= 0.31 [95%CI 0.04 - 0.57]，P = 0.023）。重度COVID-19的MR估计值未显示任何遗传相关性（OR 1.05，[95% CI 0.92 - 1.20]，P = 0.43）。然而，离群值分析显示，与其他变体相比，MUC 5 B处的IPF风险等位基因rs35705950具有不同的影响。当rs35705950被排除后，MR结果提供的证据表明IPF的遗传风险增加对COVID-19严重程度有因果影响（OR 1.21，[95% CI 1.06 - 1.38]，P = 4.24 × 10−3）。此外，MUC 5 B处的IPF风险等位基因仅在老年人中显示出对COVID-19住院治疗的明显保护作用（OR 0.86，[95% CI 0.73 - 1.00]，P = 2.99 × 10−2）。IPF最强的遗传决定因子，MUC 5 B的rs35705950，似乎可提供针对COVID-19的保护，而所有其他IPF风险基因座的组合效应似乎可提供COVID-19严重程度的风险。观察到的rs35705950的作用可能是由于气道上粘蛋白过度产生的保护作用，或由于（1）rs35705950 T高度富集的患者组进行严格的自我隔离和/或（2）rs35705950非IPF风险等位基因携带者的生存偏倚导致的选择偏倚的结果。由于IPF致病变异体对SARS-CoV-2感染的不同影响，以及可能的选择偏倚作为解释，需要进一步研究以解决MUC 5 B变异与其他IPF遗传风险因素之间的明显矛盾。诺和诺德基金会和橡树基金会。
Idiopathic pulmonary fibrosis (IPF) is a complex lung disease, characterized by progressive lung scarring. Severe COVID-19 is associated with substantial pneumonitis and has a number of shared major risk factors with IPF. This study aimed to determine the genetic correlation between IPF and severe COVID-19 and assess a potential causal role of genetically increased risk of IPF on COVID-19 severity. The genetic correlation between IPF and COVID-19 severity was estimated with linkage disequilibrium (LD) score regression. We performed a Mendelian randomization (MR) study for IPF causality in COVID-19. Genetic variants associated with IPF susceptibility (P<5 × 10−8) in previous genome-wide association studies (GWAS) were used as instrumental variables (IVs). Effect estimates of those IVs on COVID-19 severity were gathered from the GWAS meta-analysis by the COVID-19 Host Genetics Initiative (4,336 cases & 623,902 controls). We detected a positive genetic correlation of IPF with COVID-19 severity (rg=0·31 [95% CI 0·04–0·57], P = 0·023). The MR estimates for severe COVID-19 did not reveal any genetic association (OR 1·05, [95% CI 0·92–1·20], P = 0·43). However, outlier analysis revealed that the IPF risk allele rs35705950 at MUC5B had a different effect compared with the other variants. When rs35705950 was excluded, MR results provided evidence that genetically increased risk of IPF has a causal effect on COVID-19 severity (OR 1·21, [95% CI 1·06–1·38], P = 4·24 × 10−3). Furthermore, the IPF risk-allele at MUC5B showed an apparent protective effect against COVID-19 hospitalization only in older adults (OR 0·86, [95% CI 0·73–1·00], P = 2·99 × 10−2) . The strongest genetic determinant of IPF, rs35705950 at MUC5B, seems to confer protection against COVID-19, whereas the combined effect of all other IPF risk loci seem to confer risk of COVID-19 severity. The observed effect of rs35705950 could either be due to protective effects of mucin over-production on the airways or a consequence of selection bias due to (1) a patient group that is heavily enriched for the rs35705950 T undertaking strict self-isolation and/or (2) due to survival bias of the rs35705950 non-IPF risk allele carriers. Due to the diverse impact of IPF causal variants on SARS-CoV-2 infection, with a possible selection bias as an explanation, further investigation is needed to address this apparent paradox between variance at MUC5B and other IPF genetic risk factors. Novo Nordisk Foundation and Oak Foundation.
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